Mustafa, Shamimunisa Begum; (1992) The effect of platelet activating factor (PAF) on mast cells. Doctoral thesis (Ph.D), UCL (University College London).

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Abstract

In recent years, platelet activating factor (PAF) has emerged as a potent proinflammatory mediator implicated in a diverse range of human pathologies including allergy and asthma. PAF can also attract and stimulate inflammatory cells such as eosinophils and neutrophils. The present study has attempted to investigate the action of PAF on isolated histaminocytes from different species. PAF (1-100 μM) induced histamine and prostaglandin D2 release in a characteristic dose-dependent manner from rat peritoneal mast cells. Histamine release was cytotoxic at high concentrations (10 μM) of PAF but selective and non-cytotoxic at lower concentrations (5 μM). Under the latter conditions, the process was depressed at extremes of temperature, complete within approx. 10 min and f independent of pH and calcium. Analogues of PAF (C17 and C18) and lyso-PAF also induced histamine release from rat peritoneal mast cells in a dose-related manner. The non-cytotoxic release evoked by PAF and lyso-PAF from rat peritoneal mast cells was inhibited by anti-asthmatic compounds. Release induced by PAF was also inhibited by cAMP analogues, a naturally occurring flavonoid and to variable degrees by selective PAF antagonists. The cytotoxic effect of PAF was found not to be highly tissue or species specific and comparable release was induced from isolated mast cells from rat lung, mesentery and skin, guinea-pig lung and mesentery, and human intestine, lung, skin and basophils. PAF was seen to potentiate anti-IgE and concanavalin A induced histamine release from rat peritoneal mast cells. In contrast, it did not potentiate anti-IgE induced histamine release from human basophils or human lung mast cells. Thus PAF is thought to act on mast cell membranes rather than through a receptor mediated mechanism, to produce mediator release. Towards the end of this project, the effect of PAF on human neutrophils was studied. PAF (0.001-10 μM) induced a dose-related, non-cytotoxic release of β-glucuronidase from human neutrophils. The release was inhibited by the specific PAF receptor antagonist BN50730 but not by the anti-asthmatic chromone disodium cromoglycate. The present study indicates that PAF exerts its effects on human neutrophils through specific PAF receptors.

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